Hepatitis B Treatment Pearls. Agenda

Transcription

1 Hepatitis B Treatment Pearls Fredric D. Gordon, MD Vice Chair Dept. of Transplantation and Hepatobiliary Diseases Lahey Hospital & Medical Center Associate Professor of Medicine Tufts Medical School Boston, MA Agenda Phases characterizing chronic HBV infection Outcomes of patients with HBV Choosing the right patient Interesting HBV treatment questions Page 1 of 17

2 Phases of Chronic HBV Infection Immune tolerant HBeAg positive immune active Normal Elevated ALT HBV DNA HBeAg Histology Elevated, typically >1m IU/mL Elevated 20,000 IU/mL Positive Positive Minimal inflammation and fibrosis Moderate-severe inflammation or fibrosis Inactive CHB HBeAg negative immune reactivation Normal Elevated Low or undetectable <2,000 IU/mL Negative Elevated 2,000 IU/mL Negative Minimal inflammation but variable fibrosis Moderate-severe inflammation or fibrosis Terrault, et al. Hepatology 2016;63(1): Your Patients with CHB About half will fit nicely into the Phases chart It s always something. If it s not one thing, it s another. Page 2 of 17

3 Phases of Chronic HBV Infection Immune tolerant HBeAg positive immune active Inactive CHB HBeAg negative immune reactivation Normal Elevated ALT HBV DNA HBeAg Histology Normal 3,500 Elevated 42 Elevated, typically >1m IU/mL Elevated 20,000 IU/mL 15,000 Low or undetectable <2,000 IU/mL Positive Positive Negative Elevated 2,000 IU/mL Negative Minimal inflammation and fibrosis Moderate-severe inflammation or fibrosis Minimal inflammation but variable fibrosis Moderate-severe inflammation or fibrosis Terrault, et al. Hepatology 2016;63(1): Phases Are Not Always Static or Progressive Tong, et al. Dig Dis Sci 2011;56: Page 3 of 17

4 Remember These are GUIDELINES For example: Immune-active = HBeAg +, HBV DNA >20K, ALT >2x ULN Terrault, et al. Hepatology 2016;63(1): Use Good Judgment Guidelines, not requirements Elastography may be helpful but doesn t adequately address inflammation Don t be afraid to biopsy patients who don t fit in Try your best to categorize in order to facilitate proper treatment Page 4 of 17

5 Risk Factors for Progression to Cirrhosis or HCC in HBsAg-Positive Individuals Host Older age (>40 yrs) Male sex Asian/African ancestry HCC family history Clinical Cirrhosis HCV coinfection Viral HBeAg positive Higher HBV DNA Genotype B, C Precore mutation Basal core promoter mutation Other Smoking, alcohol Obesity, diabetes McClune AC, et al. Clin Liver Dis. 2010;14: Risk of HCC and Cirrhosis According to Baseline HBV DNA Cirrhosis (% per Yr) [2] HBV DNA (copies/ml) < ,000-99, , ,999 1 million HCC (% per Yr) [1] HBV DNA (copies/ml) < ,000-99, , ,999 1 million Chen CJ, et al. JAMA. 2006;295: Iloeje UH, et al. Gastroenterology. 2006;130: Page 5 of 17

6 HCC screening HBV carriers at high risk for HCC should be screened with ultrasound examination every 6-12 months. High risk populations include: Asian men over 40 years Asian women over 50 years of age Persons with cirrhosis Persons with a family history of HCC Africans over 20 years of age Any carrier over 40 years with persistent or intermittent ALT elevation and/or high HBV DNA level >2,000IU/mL Lok A.S.F. and McMahon B.J. Hepatology 2009; vol. 50 (3): 1-36 Pts With Chronic HBV Infection and Normal ALT May Have Significant Liver Disease Retrospective review of pts with chronic HBV infection Persistently normal ALT ALT x ULN ALT >1.5 x ULN 37% of pts with chronic HBV infection and persistently normal ALT had evidence of significant fibrosis (stage 2-4) or inflammation (grade 2-3) by liver biopsy Lai M, et al. J Hepatol. 2007;47: Page 6 of 17

7 USPSTF HBV Screening Recommendation The USPSTF recommends screening for HBV infection in persons at high risk for infection (Grade B recommendation) Groups at high risk for HBV infection include Persons born in countries where HBV is common (prevalence >2%) U.S. born persons not vaccinated as infants whose parents were born in countries with high prevalence of HBV infection HIV+ persons Household contacts of HBV-infected persons IVDUs MSM high risk for infection is defined as having a prevalence threshold of 2% countries with high prevalence have a prevalence 8% USPSTF, U.S. Preventive Services Task Force; IVDUs, injection drug users; MSM, men who have sex with men LeFevre ML, et al. Ann Intern Med. 2014; 27 May 2014 [Epub ahead of print] HBV Treatment Page 7 of 17

8 Goals of Treatment For Chronic HBV Infection Primary Goal Prevent adverse clinical outcomes Cirrhosis, HCC, death Markers of Success Undetectable HBV DNA Improved liver histology Normal ALT HBeAg loss or seroconversion HBsAg loss or seroconversion E Keeffe et al., Clinical Gastroenterology and Hepatology, December 2008;v6,12: Management of Chronic HBV Infection HBeAg-positive HBeAg (+) ALT <ULN HBV DNA <20,000 IU/mL ALT <ULN HBV DNA >20,000 IU/mL ALT >ULN HBV DNA >20,000 IU/mL Observe Q 3 6 mo ALT Q 6 12 mo HBeAg Q 3 mo ALT Q 6 mo HBeAg Consider biopsy if persistent or age >35 Treat if histology abnormal Liver biopsy optional Treat E Keeffe et al., Clinical Gastroenterology and Hepatology, December 2008;v6,12: Page 8 of 17

9 Management of Chronic HBV Infection HBeAg-negative HBeAg (-) ALT <ULN; HBV DNA <2,000 IU/mL Q 3 mo ALT x 3, then Q 6 12 mo if ALT still <1 x ULN ALT <ULN; HBV DNA >2,000 IU/mL Q 3 mo ALT & HBV DNA Consider biopsy if persistent DNA elevation or age >35 Treat if histology abnormal ALT >ULN; HBV DNA >2,000 IU/mL Liver biopsy optional Treat E Keeffe et al., Clinical Gastroenterology and Hepatology, December 2008;v6,12: Management of Chronic HBV Infection Patients with Cirrhosis Compensated* Decompensated HBV DNA <2,000 IU/mL HBV DNA 2,000 IU/mL Detectable HBV DNA Undetectable HBV DNA Observe or Treat Treat Treat Observe Wait List for Transplant E Keeffe et al., Clinical Gastroenterology and Hepatology, December 2008;v6,12: Page 9 of 17

10 Clinical Stage HBeAg HBV DNA ALT Recommendation Immune tolerant + >2000 IU/mL ULN Monitor Chronic hepatitis + >2000 IU/mL >ULN Treat Chronic hepatitis - >2000 IU/mL >ULN Treat Chronic hepatitis - >2000 IU/mL ULN Assess gray zone* Chronic hepatitis ± 2000 IU/mL >ULN Assess gray zone* Cirrrhosis ± Detectable NA Treat Cirrhosis ± Undetectable NA Monitor Decomp cirrhosis ± NA NA Treat Inactive carrier IU/mL ULN Monitor * If liver biopsy refused Tong, et al. Dig Dis Sci 2011;56: Hepatitis B in Asian Americans Gray Zone Tong, et al. Dig Dis Sci 2011;56: Page 10 of 17

11 FDA Approved Therapies for CHB Generic Name Trade Name Manufacturer Nucleosides/Nucleotides Date Approved for Hepatitis B Tenofovir DF VIREAD Gilead Sciences 2008 Telbivudine TYZEKA Idenix and Novartis 2006 Entecavir BARACLUDE Bristol-Myers Squibb 2005 Adefovir dipivoxil HEPSERA Gilead Sciences 2002 Lamivudine EPIVIR-HBV GlaxoSmithKline 1998 Interferons Peginterferon alfa-2a PEGASYS Roche Laboratories Interferon alfa-2b, recombinant INTRON A Schering Corporation Efficacy of Antiviral Therapies Terrault, et al. Hepatology 2016;63(1): Page 11 of 17

12 PegIFN vs Nucleos(t)ide Analogues Pro Finite course of therapy No resistance Higher rate of HBeAg loss in 1 yr Higher rate of HBsAg loss with short duration therapy* [1] PegIFN Con SQ administration Frequent AEs Contraindicated in patients with cirrhosis, in pregnancy, with acute hepatitis B, and who are immunosuppressed *Particularly for HBeAg-positive patients with genotype A infection. Risk of lactic acidosis higher in patients with advanced liver disease. [2-3] Nucleos(t)ide Analogues Pro Con PO administration Infrequent AEs ETV approved for patients with decompensated disease [2] Need for longterm or indefinite therapy Potential for drug resistance 1. Buster EH, et al. Gastroenterology. 2008;135: Entecavir [package insert] Tenofovir [package insert] Therapeutic Options Peginterferon needs to be considered as a possible initial therapy Only once chance to use interferon Advantages of peginterferon HBeAg seroconversion rate at 1 year higher than nucleos(t)ide analogues (30% versus 20%) Finite course of therapy HBsAg loss more likely Newer nucleos(t)ide analogues have greater viral suppression and lower rates of resistance but similar HBeAg seroconversion rates No data yet to support combination therapy (peginterferon + nucleos(t)ide analogues or 2 nucleos(t)ide analogues) Page 12 of 17

13 Should Immune Tolerant Patients Be Treated to Decrease Liver Complications? Immune tolerant = Elevated HBV DNA, normal ALT ( 30 for M, 19 for F), minimal inflammation and fibrosis AASLD weakly recommends treatment for age >40, normal ALT, HBV DNA 1,000,000 IU/mL and liver biopsy showing significant necroinflammation or fibrosis Terrault, et al. Hepatology 2016;63(1): Should Immune Tolerant Patients Be Treated to Decrease Liver Complications? Higher rate of HBeAg loss and seroconversion compared to controls No study demonstrates benefit with regard to: Rates of HCC Rates of cirrhosis Rates of liver-related death So.probably NOT Terrault, et al. Hepatology 2016;63(1): Page 13 of 17

14 Should Therapy be Stopped in Patients who Seroconvert HBeAg to HBeAb? YES (???) If non-cirrhotic, AND After at least one more year of normal ALT and undetectable HBV DNA Stopped Continued 0 ALT flare HBV viremia Fung et al, Am J Gastroenterol, 2009;104: Chaung et al, J Clin Gastroenterol, 2012;46: Should Therapy be Stopped in Patients who Seroconvert HBeAg to HBeAb? Yes Paucity of evidence about benefit of lifelong therapy (no change in HCC, cirrhosis, decompensation) Side effects Burden Cost No Increased risk of progression of disease Reduced durability of response Risk of HCC is higher in HBeAg positive Risk of cirrhosis is higher in HBeAg positive Optimal duration of consolidation unknown Terrault, et al. Hepatology 2016;63(1): Page 14 of 17

15 Should Therapy be Stopped in HBeAg negative Patients with Sustained HBV DNA Suppression? No Maybe, if HBsAg loss Lifelong therapy recommended High risk of virologic relapse 1, 2 Risk of decompensation 8.2% (1 yr), 12.5% (2 yr), 19.8% (5 yr) 3 1 Huang et al, J Viral Hepat 2003;10: Sanantonio, et al, J Hepatol 2000;32: Chang et al, Clin Gastroenterol Hepatol 2015;13: Algorithm for HBV Management in Women During Pregnancy Pregnant women with HBV infection 1st trimester: assess HBV replication and liver disease End of 2nd trimester: quantitative HBV DNA and ALT levels Active disease/suspected cirrhosis: consider initiating treatment with tenofovir HBV DNA <2x10 5 IU/mL* Monitor; infant receives HBIG + vaccine at birth HBV DNA >2x10 5 IU/mL* Consider initiating treatment with tenofovir, lamivudine, or telbivudine at wks Infant receives HBIG + vaccine at birth *The cut-off level of maternal HBV DNA level for initiation of therapy is unclear, and HBV DNA from 5-8 log 10 IU/mL can be considered for therapy based on physician and patient preference. Tenofovir is preferred if treatment is expected to be >12 weeks or if treatment is expected to continue while breastfeeding. Page 15 of 17

16 Recommendations for Treatment of Hepatitis B carriers Who Require Immunosuppressive or Cytotoxic Therapy (AASLD Guidelines) 38. HBsAg testing should be performed in patients who are at high risk of HBV infection prior to initiation of chemotherapy or immunosuppressive therapy. (II-3) 39. Prophylactic antiviral therapy is recommended for HBV carriers at the onset of cancer chemotherapy or of a finite course of immunosuppressive therapy. a. Patients with baseline HBV DNA <2,000 IU/mL level should continue treatment for 6 months after completion of chemotherapy or immunosuppressive therapy. (III) b. Patients with high baseline HBV DNA (>2,000 IU/mL) level should continue treatment until they reach treatment endpoints as in immunocompetent patients. (III) c. Lamivudine or telbivudine can be used if the anticipated duration of treatment is short (<12 months). (I for lamivudine and III for telbivudine) d. Tenofovir or entecavir is preferred if longer duration of treatment is anticipated. Entecavir has more rapid onset of action than tenofovir and may be more appropriate in this setting. (III) e. IFN- should be avoided in view of the bone marrow suppressive effect. (II-3) Lok ASF and McMahon BJ, Hepatol 2009;50(3):1-36 What About Renal Failure and Bone Disease on Treatment? AASLD recognizes no preference between entecavir and tenofovir regarding potential risk of renal and bone complications No significant differences in RCTs Renal failure reported in tenofovir treated patients Monitor renal function at least annually Terrault, et al. Hepatology 2016;63(1): Page 16 of 17

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